title: Adjuvant activity of naturally occurring monophosphoryl lipopolysaccharide preparations from mucosa-associated bacteria.
abstract: Natural heterogeneity in the structure of the lipid A portion of lipopolysaccharide (LPS) produces differential effects on the innate immune response. Gram-negative bacterial species produce LPS structures that differ from the classic endotoxic LPS structures. These differences include hypoacylation and hypophosphorylation of the diglucosamine backbone, both differences known to decrease LPS toxicity. The effect of decreased toxicity on the adjuvant properties of many of these LPS structures has not been fully explored. Here we demonstrate that two naturally produced forms of monophosphorylated LPS, from the mucosa-associated bacteria Bacteroides thetaiotaomicron and Prevotella intermedia, function as immunological adjuvants for antigen-specific immune responses. Each form of mucosal LPS increased vaccination-initiated antigen-specific antibody titers in both quantity and quality when given simultaneously with vaccine antigen preparations. Interestingly, adjuvant effects on initial T cell clonal expansion were selective for CD4 T cells. No significant increase in CD8 T cell expansion was detected. MyD88/Toll-like receptor 4 (TLR4) and TRIF/TLR4 signaling pathways showed equally decreased signaling with the LPS forms studied here as with endotoxic LPS or detoxified monophosphorylated lipid A (MPLA). Natural monophosphorylated LPS from mucosa-associated bacteria functions as a weak but effective adjuvant for specific immune responses, with preferential effects on antibody and CD4 T cell responses over CD8 T cell responses.
authors.affiliation: Institute for Cellular Therapeutics, Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Chilton
authors.forename: Diana M
authors.initials: DM
authors.lastname: Hadel
authors.forename: Thao T
authors.initials: TT
authors.lastname: To
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Mitchell
authors.forename: Richard P
authors.initials: RP
authors.lastname: Darveau
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001419:Bacteria / Q000276:immunology* / Q000378:metabolism; D001439:Bacteroides / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D008050:Lipid A / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D009092:Mucous Membrane / Q000276:immunology* / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D018713:Prevotella intermedia / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D014611:Vaccination / Q000379:methods
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000276:Adjuvants, Immunologic; D008050:Lipid A; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4